14-67724588-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_152443.3(RDH12):c.184C>T(p.Arg62*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000776 in 1,611,290 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000078 ( 0 hom. )

Consequence

RDH12
NM_152443.3 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:18

Conservation

PhyloP100: 2.27

Variant links:

Genes affected

RDH12 (HGNC:19977): (retinol dehydrogenase 12) The protein encoded by this gene is an NADPH-dependent retinal reductase whose highest activity is toward 9-cis and all-trans-retinol. The encoded enzyme also plays a role in the metabolism of short-chain aldehydes but does not exhibit steroid dehydrogenase activity. Defects in this gene are a cause of Leber congenital amaurosis type 13 and Retinitis Pigmentosa 53. [provided by RefSeq, Sep 2015]

RDH12 links:

GPHN (HGNC:15465): (gephyrin) This gene encodes a neuronal assembly protein that anchors inhibitory neurotransmitter receptors to the postsynaptic cytoskeleton via high affinity binding to a receptor subunit domain and tubulin dimers. In nonneuronal tissues, the encoded protein is also required for molybdenum cofactor biosynthesis. Mutations in this gene may be associated with the neurological condition hyperplexia and also lead to molybdenum cofactor deficiency. Numerous alternatively spliced transcript variants encoding different isoforms have been described; however, the full-length nature of all transcript variants is not currently known. [provided by RefSeq, Jul 2008]

GPHN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 14-67724588-C-T is Pathogenic according to our data. Variant chr14-67724588-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 2050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-67724588-C-T is described in Lovd as [Pathogenic]. Variant chr14-67724588-C-T is described in Lovd as [Likely_pathogenic]. Variant chr14-67724588-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RDH12	NM_152443.3 link	c.184C>T	p.Arg62*	stop_gained	Exon 4 of 9	ENST00000551171.6	NP_689656.2	Q96NR8A0A0S2Z613
RDH12	XM_047430965.1 link	c.184C>T	p.Arg62*	stop_gained	Exon 4 of 9		XP_047286921.1
GPHN	XM_047430879.1 link	c.1313-10607C>T		intron_variant	Intron 14 of 14		XP_047286835.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RDH12	ENST00000551171.6 link	c.184C>T	p.Arg62*	stop_gained	Exon 4 of 9	1	NM_152443.3	ENSP00000449079.1		Q96NR8
RDH12	ENST00000267502.3 link	c.184C>T	p.Arg62*	stop_gained	Exon 3 of 8	5		ENSP00000267502.3		Q96NR8

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152068

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000557

AC:

AN:

251424

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000879

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000781

AC:

114

AN:

1459104

Hom.:

Cov.:

AF XY:

0.0000661

AC XY:

AN XY:

726006

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000910

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74398

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000111

Hom.:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Leber congenital amaurosis 13

Pathogenic:9

Aug 01, 2019

Ocular Genomics Institute, Massachusetts Eye and Ear

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 03, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 22, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jul 22, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Laboratory of Genetics in Ophthalmology, Institut Imagine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Oct 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg62*) in the RDH12 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RDH12 are known to be pathogenic (PMID: 17964524, 22065924, 32014858, 34001834). This variant is present in population databases (rs104894471, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with autosomal recessive Leber congenital amaurosis or retinitis pigmentosa (PMID: 15258582, 15322982, 26497376, 29186038). ClinVar contains an entry for this variant (Variation ID: 2050). For these reasons, this variant has been classified as Pathogenic. -

Mar 27, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:4

Apr 15, 2019

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in 4/24,014 (0.017%) alleles from individuals of African background and in 13/277,094 (0.005%) global alleles, in large population cohorts and no individuals were reported to be homozygous (Lek et al., 2016); This variant is associated with the following publications: (PMID: 32865313, 31054281, 30134391, 29186038, 15258582, 29068479, 15322982, 26497376) -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RDH12: PVS1, PM3:Strong, PM2 -

Leber congenital amaurosis

Pathogenic:3

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 29, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The heterozygous p.Arg62Ter variant in RDH12 was identified by our study in 1 individual with Leber congenital amaurosis, in a compound heterozygous state with a likely pathogenic variant. Please note that this variant has been identified by a collaborative research study and was also be submitted by Massachusetts Eye and Ear. The p.Arg62Ter variant has been reported in at least 10 individuals with Leber congenital amaurosis (PMID: 15322982,15258582, 29186038, 32014858, 26497376, 30134391). The presence of this variant in at least 2 homozygotes, and in combination with a reported pathogenic variant, and in at least 1 individual with Leber congenital amaurosis increases the likelihood that the p.Arg62Ter variant is pathogenic (PMID: 15258582, 26497376, 30134391) and has been identified in 0.016% (4/24952) of African, 0.009% (11/129094) of European (Non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs104894471). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar as pathogenic by Mendellics, Invitae, OMIM, Ocular Genomics Institute, Massachusetts Eye and Ear, Blueprint Genetics (VariationID: 2050). This nonsense variant leads to a premature termination codon at position 62, which is predicted to lead to a truncated or absent protein. Loss of function of the RDH12 gene is a moderately established disease mechanism in autosomal recessive Leber congenital amaurosis. The p.Arg62Ter variant is located in a region of RDH12 that is essential to protein folding and stability, suggesting that this variant is in a functional domain and slightly supports pathogenicity (PMID: 32014858). In summary, this variant meets criteria to be classified as pathogenic for Leber congenital amaurosis in an autosomal recessive manner based on the predicted loss of function effect of this variant and the presence of this variant in the homozygous state and in combination with other pathogenic variants in affected individuals. ACMG/AMP Criteria applied: PVS1_strong, PM1_supporting, PM3_strong (Richards 2015). -

Aug 21, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RRDH12 c.184C>T (p.Arg62X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 5.6e-05 in 251424 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in RDH12 causing Leber Congenital Amaurosis (5.6e-05 vs 0.0016), allowing no conclusion about variant significance. c.184C>T has been reported in the literature in multiple individuals affected with Leber Congenital Amaurosis, Retinitis pigmentosa or Inherited retinal disease (Jin_2022, Lin_2024). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 35006499, 38219857). ClinVar contains an entry for this variant (Variation ID: 2050). Based on the evidence outlined above, the variant was classified as pathogenic. -

Retinal dystrophy

Pathogenic:2

Jan 01, 2021

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 04, 2018

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.36

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.82

Vest4

0.88

GERP RS

2.9

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over